Many malignant sarcomas such as angiosarcomas are refractory to currently available treatments. However, sarcomas possess unique vascular properties, which indicate they may be more responsive to therapeutic agents that target endothelial function. MEKs have been demonstrated to play an essential role in growth and vascularization of carcinomas. We hypothesize that signaling through multiple MEK pathways is also essential for growth and vascularization of sarcomas. LeTx is a toxin, which targets receptors that are highly expressed in tumor endothelial cells. However, unlike small molecule inhibitors, which target a single biochemical pathway, LeTx inactivates multiple MEK pathways, which are essential for tumor cell proliferation and vascularization. These properties of LeTx indicate that it is uniquely suited to block sarcoma growth and vascularization. The objective of this proposal is to define the role of MEK signaling in growth and vascularization of human sarcoma and determine whether inhibition of multiple MEKs by agents such as LeTx may form the basis of a novel and innovative therapeutic approach in the treatment of human sarcoma. To do this we will define the basic relationship between signal transduction through MEK pathways and growth and vascularization of human sarcoma-derived cell lines using in vitro and in vivo models. Then, we will apply the concepts we will have derived from these models and extend them to the study of a large number and variety of archived clinical sarcoma samples to establish unifying features of prognostic value.